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"Infection and Inflammation in Atherosclerosis"

Award Number: R01HL076801
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2005
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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"Infection and Inflammation in Atherosclerosis" - DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent interest has focused on chronic infectious diseases such as periodontal infection as potential contributors to CAD since traditional risk factors including hypercholesterolemia, smoking, and hypertension fail to fully explain the incidence of CAD. Epidemiological studies indicate that individuals with periodontal infection are 30 to 100% more likely to have CAD. During the past funding cycle, our findings linked NOD2, exposure to oral Porphyromonas gingivalis (P.g.), ApoE, and fatty diets with inflammatory changes to both bone loss and atherosclerosis. ApoE-/- mice injected i.p. with MDP to stimulate NOD2 and given weekly oral gavage of P.g. for 15 weeks displayed a reduction of serum cholesterol, inflammatory cytokines, alveolar bone loss, and atherosclerotic lesions in the aorta and aortic sinus compared with ApoE-/- mice orally challenged with P.g. but injected with saline. NOD2 deficiency in this model significantly aggravated bone loss and atherosclerosis. While MDP is an interesting target for therapeutic discovery, analogs with higher anti-inflammatory activity (e.g.TNF) and enhanced pharmacokinetic stability are certainly required. This is further justified by the side effects of the current anti-TNF- antibody therapies. We have recently generated novel MDP analogs and identified a candidate with significant anti-TNF and NFB properties. Active MDP analogs will be used to help characterize the pathway responsible for the MDP anti-inflammation property. To test our hypothesis we propose the following aims: Aim 1. Optimizing biological activity of MDP: We will continue medicinal chemistry and biochemical screening efforts to obtain a selective anti-inflammatory MDP compound(s) and optimize several scaffolds based on MDP. Aim 2. Determine signaling pathways of MDP and MDP analogs; and Aim 3. Preclinical testing of optimized compounds: A limited number of MDP analogs found in vitro to robustly reduce TNF production will be tested in our murine models of periodontal disease (PD) and atherosclerosis. Our goal is to elucidate the mechanism of action of optimized MDP compounds, a step towards identifying novel anti-inflammatory compounds suitable for clinical development. This will position us to apply this understanding in a human clinical trial setting, where we have considerable experience.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	13	12/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	13	5/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $528,516 )
2018	2018	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	13	5/23/2018	NON-COMPETING CONTINUATION	$528,516
														Subtotal = $528,516

Issue Date FY: 2017 ( Subtotal = $536,226 )
2017	2017	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	003	12	5/26/2017	NON-COMPETING CONTINUATION	$536,226
2017	2016	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	002	11	11/28/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$354,086
2017	2016	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	001	10	11/28/2016	NON-COMPETING CONTINUATION	-$104,051
2017	2015	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	9	11/28/2016	COMPETING CONTINUATION	-$250,035
														Subtotal = $536,226

Issue Date FY: 2016 ( Subtotal = $531,251 )
2016	2016	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	002	11	7/23/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$427,200
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	10	7/22/2016	NON-COMPETING CONTINUATION	-$426,077
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	10	5/13/2016	NON-COMPETING CONTINUATION	$530,128
														Subtotal = $531,251

Issue Date FY: 2015 ( Subtotal = $527,549 )
2015	2015	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	9	8/20/2015	COMPETING CONTINUATION	$527,549
														Subtotal = $527,549

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	8	7/14/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $402,188 )
2012	2012	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	8	6/28/2012	NON-COMPETING CONTINUATION	$402,188
														Subtotal = $402,188

Issue Date FY: 2011 ( Subtotal = $406,250 )
2011	2011	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	7	7/28/2011	NON-COMPETING CONTINUATION	$406,250
														Subtotal = $406,250

Issue Date FY: 2010 ( Subtotal = $406,250 )
2010	2010	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	6	7/30/2010	NON-COMPETING CONTINUATION	$406,250
														Subtotal = $406,250

Issue Date FY: 2009 ( Subtotal = $406,250 )
2009	2009	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	5	8/14/2009	COMPETING CONTINUATION	$406,250
2009	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	8/14/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $406,250

Issue Date FY: 2008 ( Subtotal = $382,828 )
2008	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	2/12/2008	NON-COMPETING CONTINUATION	$382,828
														Subtotal = $382,828

Issue Date FY: 2007 ( Subtotal = $382,828 )
2007	2007	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	1/17/2007	NON-COMPETING CONTINUATION	$382,828
														Subtotal = $382,828

Issue Date FY: 2006 ( Subtotal = $394,262 )
2006	2006	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	1/23/2006	NON-COMPETING CONTINUATION	$394,262
														Subtotal = $394,262

Issue Date FY: 2005 ( Subtotal = $403,750 )
2005	2005	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	1/6/2005	NEW	$403,750
														Subtotal = $403,750

Grand Total All Awards = $5,308,148

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"Infection and Inflammation in Atherosclerosis"

Award Number: R01HL076801

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2005

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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